The present invention generally relates to novel pyridopyrimidine-based compounds, pharmaceutical compositions containing such compounds, methods for preparing such compounds and methods for using these compounds, alone or in combination with other therapeutic agents, for the treatment or prevention of symptoms or manifestations associated with diseases or disorders affected by cytokine intracellular signaling.
Cellular signals necessary for cell growth, differentiation, response to bioregulatory molecules, infectious agents and physiological stress involve various biochemical processes. The ability to respond appropriately to such signaling events challenge the survival of the cell and ultimately the organism. Perturbations in the normal regulation of these specific responses can result in pathogenic events which lead to acute and chronic disease.
For example, inflammatory responses are a component of the pathogenesis of many vertebrate disorders/diseases, including those in humans. In its broadest meaning, the term xe2x80x9cinflammationxe2x80x9d denotes local as well as systemic responses, increased blood flow, vasodilation, fluid transudation from the vessels, infiltration of the tissues by leukocytes and, in some severe cases, intravascular thrombosis, damage to the blood vessels and extravasation of blood characterize local inflammation. The systemic inflammatory response, also denoted as an acute phase response, is characterized by various reactions including, for example, fever, leukocytosis and release of acute phase reactants into the serum. In severe cases, shock and death may occur. See Heremans et al., Lymphokine Research 8(3): 329-333 (1989). Diseases involving inflammation are particularly harmful when they afflict the respiratory system, resulting in obstructed breathing, hypoxemia, hypercapnia and lung tissue damage. Obstructive diseases of the airways are characterized by airflow limitation (i.e., airflow obstruction or narrowing) due to constriction of airway smooth muscle, edema and hypersecretion of mucous leading to increased work in breathing, dyspnea, hypoxemia and hypercapnia. While the mechanical properties of the lungs during obstructed breathing are shared between different types of obstructive airway diseases, the pathophysiology can differ. The inflammatory response is believed to be controlled by a variety of cellular events characterized by the influx of certain cell types and mediators, the presence of which can lead to tissue damage and sometimes death. Cytokines are believed to be primary factors in the biochemical cascade of events that regulate inflammatory responses.
Cytokines are a class of secreted, soluble proteins produced by a variety of cells in response to many different kinds of inducing stimuli, including environmental, mechanical, and pathological stresses. Lymphoid, inflammatory and hemopoietic cells secrete a variety of cytokines that regulate the immune response by controlling cell proliferation, differentiation and effector functions. For example, regulatory cytokines produced in response to T cell stimulation during an immune response can be immunosuppressive or immunostimulatory. The immune response and acute phase response associated with altered cytokine levels can occur, for example, due to disuse deconditioning, organ damage such as that associated with transplantation, cancer treatment, septic shock and other bacterially related pathologies, adverse drug reactions, nitric oxide mediated tissue damage and diabetes. Some cytokines induce or release other known mediators of inflammation. These systems are controlled by related feedback mechanisms. Thus, it is believed that inflammatory responses are not a result of a single cytokine being released in large quantities, but rather to a set of cytokines collectively acting via a network of intercellular signals to incite the inflammatory response.
Cytokines are well known in the art and include, but are not limited to, the tumor necrosis factors (TNFs), colony stimulating factors (CSFs), interferons (INFs), interleukins (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, and IL-15), transforming growth factors (TGFs), oncostatin M (OSM), leukemia inhibiting factor (LIF), platelet activating factor (PAF) and other soluble immunoregulatory peptides that mediate host defense responses, cell regulation and cell differentiation. See, e.g., Kuby, Immunology 2d ed. (W. H. Freeman and Co. 1994). Cytokines are normally present in very low concentrations in a tissue and their effects are mediated through binding to high affinity receptors on specific cell types. Various cytokines such as the interleukins (IL), interferons (IFN), colony stimulating factors (CSF) and tumor necrosis factors (TNF) are produced during immune, inflammatory, repair and acute phase responses and they control various aspects of these responses. Following induction of such an immune, inflammatory, repair or acute phase response, the concentrations of various cytokines can increase or decrease at different times. For example, increased levels of cytokines are associated with a variety of situations such as space flight, immobilization, spinal cord injury, and bed rest, which result in disuse deconditioning. During space flight, for example, TNF, IL-6, and IL-2 levels increase upon a subject""s initial exposure to weightlessness and again upon return from space. Altered levels of cytokines have also been linked to abnormal bone metabolism and the rapid decalcification that occurs during immobilization, spinal cord injury, or long-term bed rest. Similarly, cytokine levels are altered during chronic states such as during repair and autoimmune reactions to organ damage, nephrotoxicity associated with the administration of cyclosporine to transplant subjects, cancer chemotherapy, as well as in individuals that are obese or suffering from diabetes, septic (endotoxic) shock or glomerulonephritis.
Cytokines, including the TNFs, CSFs, interferons and interleukins mediate host defense responses, cell regulation and cell differentiation. For example, these cytokines can induce fever in a subject, can cause activation of T cells, B cells and macrophages, and can even affect the levels of other cytokines, which result in a cascade effect whereby other cytokines mediate the biological levels and actions of the first cytokine.
Cytokines may regulate the immune response through immunostimulatory or immunosuppresive effects. For example, IL-10 can block activation of many of the inflammatory cytokines including TNF, IL-1 and IL-6, while upregulating anti-inflammatory cytokines, such as IL-4. IL-10, which is produced by macrophages and other cell types, also stimulates the proliferation of mast cells and thymocytes and inhibits various functions of monocytes and macrophages. As a consequence of this monocyte and macrophage inhibition, the activity of T cells is also affected. The full scope of the role of IL-10 in the immune system is only beginning to be understood.
Cytokines have multiple biological activities and interact with more than one cell type. Thus, it has not been possible to target one particular cytokine or cell type to prevent the damaging side effects of treatment. A better approach for preventing damage due to the unwanted and uncontrolled over-suppression or over-stimulation of cytokine activity would be to regulate the expression of the relevant or controlling cytokine or cytokines involved in an immune response without eliminating or over-expressing any one cytokine. Such a treatment would not create or aggravate a pathological or ongoing immune response. In this way, pathological immune-mediated effects, such as immunosuppression or autoimmune reactions, can be prevented and homeostasis can be maintained.
Corticosteroids have been used to modulate cytokine expression. However, they can cause complete immunosuppression and have other undesirable side effects, such as inducing xe2x80x9cwastingxe2x80x9d syndrome, diabetes and osteoporosis. For example, steroid therapy is a common treatment for MS because it is believed that steroids alter the trafficking of cells into the brain or reduce the secretion of cytokines by inflammatory cells in areas of inflammation. Although their effect in reversing some of the acute symptoms of autoimmune disease, such as MS, are well known, their side effects have precluded long-term use. Similarly, non-steroidal anti-inflammatory drugs (NSAID), are effective in treating inflammation and pain. However, NSAIDs also cause undesirable side effects by inhibiting prostaglandin production, which can lead to potentially severe complications including gastric ulceration, bleeding and renal failure.
One particular cytokine, IL-12, also referred to as natural killer cell stimulatory factor (xe2x80x9cNKSFxe2x80x9d) or cytotoxic lymphocyte maturation factor (xe2x80x9cCLMFxe2x80x9d), is a potent immunoregulatory molecule that plays a role in a wide range of diseases. In particular, IL-12 is a heterodimeric cytokine that is produced by phagocytic cells, e.g., monocytes/macrophages, B-cells and other antigen-presenting cells (xe2x80x9cAPCxe2x80x9d) and is believed to act as a proinflammatory cytokine. It has several effects including 1) enhanced proliferation of T cells and NK cells, 2) increased cytolytic activities of T cells, NK cells, and macrophages, 3) induction of IFN-.gamma. production and to a lesser extent, TNF-xcex1 and GM-CSF, and 4) activation of TH1 cells. See Trinchieri, G., et al., Blood, 84:4008-4027 (1994). IL-12 has been shown to be an important costimulator of proliferation in Th1 clones (Kennedy et al., Eur. J. Immunol., 24:2271-2278, 1994) and leads to increased production of IgG2a antibodies in serum (Morris, S. C. , et al., J. Immunol., 152:1047 (1994). Administration of IL-12 also decreases production of IgG1 antibodies (Morris, S. C., et al., J. Immunol., 152:1047 (1994); McKnight, A. J., J. Immunol. 152:2172 (1994)), indicating suppression of the Th2 response. It is also believed that IL-12 plays a specific role in diseases exhibiting an inflammatory component, namely, diseases that exhibit cell-mediated inflammatory responses, such as, multiple sclerosis, diabetes, chronic inflammatory bowel disease, etc.
IL-12 affects both natural killer cells (xe2x80x9cNK cellsxe2x80x9d) and T-lymphocytes (xe2x80x9cT cellsxe2x80x9d), and stimulates IFN-xcex3 production by both of these cell types. For example, in NK cells, IL-12 stimulates: NK cell proliferation, membrane surface antigen up-regulation, LAK cell generation and NK cell activity elevation; induces IFN-xcex3 and TNF-xcex1 production and the growth and expansion of either resting or activated NK cells; and increases soluble p55 and soluble p75 TNF receptor production and NK cell cytotoxicity. See RandD Systems Catalog, pp. 67-69 (1995). T cells recognize antigens via interaction of a heterodimeric (alpha/beta, or gamma/delta) receptor with short peptide antigenic determinants that are associated with major histocompatibility complex (xe2x80x9cMHCxe2x80x9d) molecules. Mature T cells can be divided broadly into two functional categories by the presence of two mutually exclusive antigens on their cell surface, CD4 (helper) and CD8 (cytotoxic). The CD4 and CD8 antigens regulate T cell interactions with MHC and their mutually exclusive expression derives from their strict specificity for MHC. Class II MHC-restricted T cells are primarily CD4+ (a.k.a. xe2x80x9chelper cellsxe2x80x9d) and class I MHC-restricted T cells are CD8+ (a.k.a. xe2x80x9ccytotoxic cellsxe2x80x9d). Mature T cells may be further distinguished by their effector phenotypes, e.g., pro-/anti-inflammatory or suppressor cells.
As mentioned above, IL-12 also affects T cells, including stimulation of T cell IFN-xcex3 production in response to antigen. While CD8+ T cells are associated with cytotoxicity functions, CD4+ T cells are associated with helper function and secrete various cytokines that regulate and modulate immune responses. CD4+ T cells can be further subdivided into T helper 1 (Th1) and T helper 2 (Th2) subsets, according to the profile of cytokines they secrete. Therefore, Th1 cells produce predominantly inflammatory cytokines, including IL-2, TNF-xcex1 and IFN-xcex3, while Th2 cells produce anti-inflammatory cytokines such as IL-4, IL-5, IL-10, and IL-13 that are linked to B cell growth and differentiation.
The Th1 and Th2 CD4+ T cell subsets are derived from a common progenitor cell, termed Th0 cells. During an initial encounter with an antigen, the differentiation into Th1 and Th2 is controlled by the opposing actions of two key cytokines, namely IL-12 and IL4, which induce the differentiation of Th0 into Th1 and Th2, respectively. The development of Th1 and Th2 cells is primarily influenced by the cytokine milieu during the initial phase of the immune response, in which IL-12 and IL-4, respectively, play decisive roles. The cytokines produced by each Th-cell phenotype are inhibitory for the opposing phenotype. For example, Th1 cytokines enhance cell-mediated immunities and inhibit humoral immunity. Th2 cytokines enhance humoral immunity and inhibit cell-mediated immunities. See Trembleau et. al., Immunology Today 16(8): 383-386 (1995).
Some human disorders/diseases that arise from effects of the immune system are mediated by anti-inflammatory responses, including atopy. This T cell mediated immune response is called anti-inflammatory because the cytokines released by anti-inflammaotry effector T cells, IL-4 and IL-10 act to suppress the development of inflammatory responses. Atopy is a genetically determined state of hypersensitivity to environmental allergens. Type-1 allergic reactions are associated with the IgE antibody production, eosinophilia and a group of diseases including, without limitation, asthma, hay fever, and atopic dermatitis. Anti-inflammatory responses also arise from infection with extracellular pathogens, like bacteria and worms. Anti-inflammatory responses are mediated by differentiated T cells and are called T2 responses. T2 (both Th2 and Tc2) responses are initiated by the release of the cytokine IL-4 from activated T and B cells and they direct and control B cell responses to infection. T2 responses also stimulate the release of IgE, histamines and other allergic effector molecules.
Furthermore, CD4+ Th1 cells play a role in the pathogenesis of immunological disorders. These cells primarily secrete cytokines associated with inflammation such as IFN-xcex3, TNF-xcex1, TNF-xcex2 and IL-2. IFN-xcex3 is an important component of the inflammatory response and resultant pathology of those diseases exhibiting an inflammatory response. Heremans, et al. In addition to its role in inflammatory response, IFN-xcex3 also contributes to phagocytic cell activation (i.e., macrophage activation), and up-regulation of MHC expression on the surface of antigen-presenting cells (xe2x80x9cAPCxe2x80x9d) and other cells. Further, this cytokine is implicated generally in inflammatory immune responses, and in autoimmune diseases, such as multiple sclerosis (xe2x80x9cMSxe2x80x9d), specifically. See Owens et al., Neurologic Clinics, 13(1):51-73 (1995). Furthermore, steroid treatment broadly attenuates cytokine production, but it cannot modulate it selectively, e.g., just the Th0, the Th1 or the Th2 pathways.
IL-12 also plays a role in the induction of Th1-cell-mediated autoimmunity. Research evidence points to a critical role for IL-12 in the pathogenesis of rodent models of Th1-mediated autoimmune diseases such as type-1 diabetes, multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and acute graft-versus-host disease. Thus, Th1 cells are believed to be involved in the induction of experimental autoimmune diseases, as demonstrated in adoptive transfer experiments demonstrating the CD4+ cells producing Th1-type lymphokines can transfer disease, as shown in models of experimental autoimmune disease, such as experimental allergic encephalomyelitis (xe2x80x9cEAExe2x80x9d) (also known as experimental allergic encephalitis) and insulin-dependent diabetes mellitus (xe2x80x9cIDDMxe2x80x9d). See Trinchieri, Annu. Rev. Immunol. 13(1):251-276 (1995). For instance, EAE is an inflammatory T cell mediated, paralytic, demyelinating, autoimmune disease that can be induced in a number of rodents as well as primates. Owens et al. One of the ways that EAE can be induced is by immunization of animals with myelin basic protein (xe2x80x9cMBPxe2x80x9d). Likewise, administration of IL-12 induces rapid onset of IDDM in 100% of NOD female mice. Thus, one goal of immunotherapy research and development efforts has been to limit inflammatory responses while leaving the specificity of the immune system, deemed necessary for host protection, intact.
Other treatments that target immune system components include lymphocyte cytotoxic drugs such as cyclophosphamide and azathioprine. These drugs act like xe2x80x9csledgehammersxe2x80x9d in that they suppress the entire immune system and raise problems that attend broad-spectrum immunosuppression therapies. The same problems also are likely with newer therapies such as cyclosporine, anti-CD4 monoclonal antibodies, and others. Other treatments for IL-12 mediated diseases, including MS, can involve the administration of anti-IL-12 antagonists such as antibodies. Anti-IL-12 antibodies have been shown to inhibit the development of IDDM and EAE. See Trinichieri. However, antibody based immunotherapy may result in immune complex formation and deposition, thus leading to glomerulonephritis, vasculitis and arthritis.
Moreover, symptomatic treatment with beta-agonists, anticholinergic agents and methyl xanthines have been clinically beneficial for the relief of discomfort but fail to stop the underlying inflammatory processes that cause the disease. The frequently used systemic glucocorticosteroids have numerous side effects, including, but not limited to, weight gain, diabetes, hypertension, osteoporosis, cataracts, atherosclerosis, increased susceptibility to infection, increased lipids and cholesterol, and easy bruising. Aerosolized glucocorticosteroids have fewer side effects but can be less potent and have side effects, such as thrush.
The use of anti-inflammatory and symptomatic relief reagents is a serious problem because of their side effects or their failure to attack the underlying cause of an inflammatory response. Other anti-inflammatory agents, such as cromolyn and nedocromil are much less potent and have fewer side effects. Anti-inflammatory agents that are primarily used as immunosuppressive agents and anti-cancer agents (i.e., cytoxan, methotrexate and Immuran) have also been used to treat inflammation. These agents, however, have serious side effect potential, including, but not limited to, increased susceptibility to infection, liver toxicity, drug-induced lung disease, and bone marrow suppression. Such drugs have found limited clinical use, for example, in the treatment of most airway hyperresponsiveness lung diseases.
To prevent pathological conditions or disruption of normal immune mediated functions caused by the aberrant expression of cytokines as described above, it would be advantageous if cytokine levels could be manipulated and efficaciously controlled. Thus, a need exists for agents that can regulate the activity of cytokines in a subject without causing undesirable side effects. Furthermore, a need exists for identifying agents which can be used in the treatment of pathologies and conditions associated with altered cytokine levels. In particular, there remains a need for novel therapeutic compounds and methods that ameliorate or inhibit the deleterious effects of responses mediated by specific cytokines, such as, for example, IL-12 or IL-4, without adversely affecting the other components of the immune system that are deemed necessary for protecting the host and without the attendant disadvantages of conventionally available compounds and methods.
It is an object of the present invention to provide novel therapeutic compounds that are stable and/or metabolically stable, including pharmaceutical compositions thereof and methods useful for inhibiting cytokine signaling.
It is another object of the present invention to provide novel therapeutic compounds, pharmaceutical compositions thereof and methods that are capable of limiting the inflammatory or anti-inflammatory response of a subject without adversely affecting the specificity of the immune system deemed necessary for protecting the subject.
It is a further object of the present invention to provide novel therapeutic compounds, pharmaceutical compositions thereof and methods that are capable of treating or preventing disease or conditions such as asthma or diabetes (IDDM and NIDDM).
The above and other objects are accomplished by a compound, including pharmaceutically acceptable derivatives (e.g., racemic mixtures, resolved enantiomers, diastereomers, tautomers, salts and solvates thereof) or prodrugs thereof, having the following formula: 
wherein:
the dashed lines, i.e., xe2x80x9c - . - . - . xe2x80x9d, represent either a single or double bond;
R1 is selected from a member of the group consisting of hydrogen, hydroxyl, methoxyl, alkylaminoalkyl, Nxe2x80x94OH, acylamino group, cyano group, sulfo, sulfonyl, sulfinyl, sulfhydryl (mercapto), sulfeno, sulfanilyl, sulfamyl, sulfamino, and phosphino, phosphinyl, phospho, phosphono and xe2x80x94NRaRb, wherein each of Ra and Rb may be the same or different and each is selected from the group consisting of hydrogen and optionally substituted: alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclic group.
R2 and R3 are independently selected from a member of the group consisting of halo, thio, OXO, C(1-20)alkyl, C(1-20)hydroxyalkyl, C(1-20)thioalkyl, C(1-20)alkylthio, C(1-20)alkylamino, C(1-20)alkylaminoalkyl, C(1-20)aminoalkyl, C(1-20)aminoalkoxyalkenyl, C(1-20)aminoalkoxyalkynyl, C(1-20)diaminoalkyl, C(1-20)triaminoalkyl, C(1-20)tetraminoalkyl, C(1-20)aminotrialkoxyamino, C(1-20)alkylamido, C(1-20)alkylamidoalkyl, C(1-20)amidoalkyl, C(1-20)acetamidoalkyl, C(1-20)alkenyl, C(1-20)alkynyl, C(1-20)alkoxyl, C(1-20)alkoxyalkyl, and C(1-20)dialkoxyalkyl.
R4 may be hydrogen or an optionally substituted member of the group consisting of alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl, and heterocyclic group.
The above novel compounds of the present invention act as, inter alia, cytokine regulatory agents to regulate the aberrant or altered expression of one or more cytokines that may occur in various conditions, including, for example, pathologies, immune responses and inflammatory responses. Such conditions are considered together for purposes of the present invention in that they are characterized, in part, by altered or aberrant cytokine activity and, therefore, are amenable to regulation by one or more cytokine regulatory agents. As used herein, the term xe2x80x9ccharacterized byxe2x80x9d means contributes or affects, at least in part. Although cytokine contribution can be, it does not have to be, the only, primary, or even a major factor or cause of a condition treatable by the compounds of the present invention. For example, it is well understood in the art that an infection has altered cytokine levels and is, therefore, a condition characterized by cytokine activity, but that cytokine activity is only a part of the infectious condition. As used herein, the term xe2x80x9ccondition characterized by altered or aberrant cytokine activityxe2x80x9d includes all cytokine regulated or modulated pathologies and injuries, including the immune, inflamatory and healing processes associated with an injury. The skilled artisan can recognize such a condition by detecting an increased or decreased level of activity of a particular cytokine as compared to the normal level of the cytokine expected to be found in a healthy individual. Methods for determining such normal levels are well known in the art.
The present invention particularly provides novel therapeutic compounds having a pyridopyrimidine-based structural core and methods of using such tricylic compounds for affecting, preventing, treating, inter alia, the cellular responses associated with Th1 or Th2 cell-mediated diseases, without affecting the other components of the immune system that are deemed necessary for host protection. The compounds and methods of the present invention are particularly characterized by an ability to inhibit IL-12 or IL-4 signaling. Without wishing to be bound by theory, it is believed that the therapeutic compounds of the present invention short-circuit the inflammatory cascade by Th1, T2, Th2 or T2 cell development, emphasizing the present invention""s importance in disease therapy by inhibiting cytokine signaling in the regulation of inflammatory or anti-inflammatory disorders. Specifically, the pyridopyrimidine-based compounds of the present invention may impede signaling that induces differentiation of T cells to Th1 or Th2 cells. For example, differentiated Th1 cells produce high levels of IFN-xcex3, which provokes inflammation, a component of many disease conditions that the inventive compounds and methods target. Moreover, the pyridopyrimidine-based compounds of the present invention act to ameliorate the insulin secretory defects found in Type-2 diabetes myelitis (NIDDM) that are believed to be associated with defects in fatty acid metabolism by affecting insulin secretion and glucose tolerance.
The present invention also achieves the above and other objects by, inter alia, providing novel therapeutic compounds and methods for treating or preventing disease conditions characterized by altered or aberrant cytokine activity. Examples of such disease conditions include, but are not limited to: (1) inflammatory diseases or disorders, such as, for example, arthritis, asthma, chronic inflammatory diseases, chronic intestinal inflammation, psoriasis, septic shock, septicemia, allergic contact dermatitis, ankylosing spondylitis and adult respiratory distress syndrome; (2) autoimmune diseases or disorders or other patho-immunogenic diseases or reactions, such as, for example, allergic reactions or anaphylaxis; allergic encephalomyelitis, amyotrophic lateral sclerosis, bullous pemphigold, Celiac disease, chronic active hepatitis, chronic thyroiditis, gastritis, Goodpastures syndrome, graft-versus-host disease (acute and/or chronic), glomerulonephritis; hemolytic anemia, immune thrombocytopenia purpura, inflammatory bowel disease (e.g., Crohn""s Disease and ulcerative colitis), isopathic thrombocytopenic purpura, juvenile arthritis, lupus disorders (e.g., systemic lupus erythematosus), male infertility (autoimmune), multiple sclerosis, myasthenia gravis, neutropenia, pemphigus vulgaris, parasitic mediated immune dysfunctions (e.g. Chagas"" Disease), pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, primary antiphospholipid syndrome, primary biliary cirrhosis, primary Sjogren""s syndrome, Reiter""s disease, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, thrombocytopenia, Sjorgens disease, sympathetic ophthalmia, thyroid diseases (e.g., Graves"" and Hashimoto""s disease), Type-1 (IDDM) and Type-2 (NIDDM) diabetes mellitus, uveitis, and viral myocarditis (Cocksakie B virus response); (3) neurodegenerative diseases such as, for example, Alzheimer""s disease, Parkinson""s disease, and primary lateral sclerosis; (4) chronic lymphocytic leukemia (CLL), hairy cell leukemia, prolymphocytic leukemia, well differentiated lymphocytic lymphomas, infectious mononucleosis, human immunodeficiency virus; (5) adverse reactions associated with cancer chemotherapy; (6) diseases such as atherosclerosis and diabetes that are believed to be mediated by free radicals and nitric oxide action; (7) bacterial endotoxic sepsis and related shock; (8) pain; (9) Type-1 hypersensitivity allergic reactions such as asthma, hay fever, eczema, urticaria, food allergy and atopic dermatitis; (10) cachexia; and (11) angiogenesis, including neoplasia; metastasis; etc. The methods of using the compounds of the present invention are particularly useful in the treatment of autoimmune diseases, MS, diabetes mellitus (Type-1 or -2) or asthma. The compounds of the present invention may be employed in any suitable conventional manner for the treatment of the above diseases. Such methods of treatment, their dosage levels and requirements may be selected by those of skill in the art from available methods and techniques that are further described below, that are known in the art or that are readily determinable using routine experimentation.
The present invention also includes a method for inhibiting a cellular process or an activity mediated by cytokine, the method comprising:
(a) contacting cytokine responsive cells with a compound as defined in claim 1; and
(b) determining that the cellular process or activity mediated by the cytokine is inhibited;
wherein said activity is the secretion of a cytokine selected from the group consisting of tumor necrosis factor, colony stimulating factor, interferon, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, transforming growth factor, oncostatin M, leukemia inhibiting factor, and platelet activating factor.
The present invention further includes a method for treating a T1 or T2 cell-mediated response in a mammal in need of such treatment, the method comprising: administering to the mammal a therapeutically effective amount of the compound of claim 1, wherein said compound is capable of inhibiting an IL-12 mediated cellular process or activity, thereby inhibiting the response.
Additional aspects, embodiments and advantages of the present invention will be set forth, in part, in the description that follows, or may be learned from practicing or using the present invention. The objects and advantages may be realized and attained by means of the features and combinations particularly pointed out throughout this written description and the appended claims. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not to be viewed as being restrictive of the invention as claimed.